"Programmed" as opposed to "accidental" death of cells is a normal and essential biological feature in the differentiation and maintenance of cellular populations in multicellular organisms. The normal turnover of epithelia such as skin or the gut lining involves the programmed death of terminally differentiated cells. Similarly, many cells of the hematopoietic system have short life expectancies, and their death is also programmed. In the developing nervous system, large numbers of neurons undergo programmed cell death (Oppenheim, Trends Neurosci. 8:487-493 (1985)).
Programmed death can often be distinguished morphologically from accidental death (Wyllie, Int. Rev. Cytol. 17:755-785 (1987); Wyllie, et al., Int. Rev. Cytol. 68:251-300 (1980)). In accidental death, the major target organelle seems to be the mitochondrion, which swells until it is dysfunctional, leading to death and lysis of the cell (necrosis). In contrast, programmed death is usually characterized by an early collapse of the nucleus, with extreme condensation of chromatin and loss of the nucleolus. The cell shrinks, in contrast to swelling in necrosis, and is phagocytosed before it lyses. This phenomenon, first referred to as shrinkage necrosis, is now called apoptosis (Kerr, et al., Br. J. Cancer 26:239-257 (1972)). The nuclear collapse in apoptosis is probably due, in most cell types, to fragmentation of the chromatin into units of single or multiple nucleosomes observable by electrophoresis in agarose gels (Cohen and Duke, J. Immunol. 132:38-42 (1984); Wyllie, Nature 284:555-556 (1980)). This is one of the ways in which apoptosis can be distinguished from necrosis. Chromatin fragmentation may be the result of activation of an endogenous Ca.sup.2+ and Mg.sup.2+ -dependent endonuclease (Compton and Cidlowski, J. Biol. Chem. 262:8288-8292 (1987); Hewish, Biophys. Res. Commun. 52:475-481 (1973)).
An example of programmed cell death is demonstrated in rodent thymocytes. The death program can be initiated in these cells by a number of inductive stimuli, including exposure to glucocorticoids (Cohen and Duke, J. Immunol. 132:38-42 (1984); Wyllie, Nature 284:555-556 (1980)) and irradiation (Sellins and Cohen, J. Immunol. 139:3199-3206 (1987)). In these instances the death program (apoptosis) can be prevented by the presence of inhibitors of RNA or protein synthesis (Cohen and Duke, J. Immunol. 132:38-42 (1984), Sellins and Cohen, J. Immunol. 139:3199-3206 (1987)). This suggests that genes, normally silent or negatively regulated, are activated by inductive stimuli leading to the production of proteins that mediate or act directly in the death process.